Various cytidine antimetabolites have been developed to treat malignant tumors or viral diseases; cytarabine, gemcitabine and the like are clinically used as antitumor (anticancer) agents and zalcitabine, lamivudine and the like as antiviral agents.
However, many of these cytidine antimetabolites cannot sufficiently exert the efficacy thereof themselves or are required to be administered at high doses because they are susceptible to metabolism and excretion in vivo despite exhibiting strong in vitro activities. By way of example, gemcitabine has a strong activity of suppressing cell growth, in vitro, comparable to those of anticancer agents such as paclitaxel and doxorubicin, but needs to be clinically given at a high dose of 1,000 mg/m2 body surface area for each administration. This is considered to be due to that the amino group at the 4-position of the base is metabolized and inactivated by cytidine deaminase, a metabolizing enzyme for 2′-deoxycytidine to reduce the in vivo availability thereof (see Non-Patent Document 1).
Binding an agent to a polymer can sometimes improve pharmacokinetics thereof in vivo to enhance the therapeutic effect. Non-Patent Document 2 describes a polymeric derivative in which cytarabine is bound to a polyglutamic acid having an average molecular weight of about 30,000. However, a polymeric derivative of an agent sometimes induces hypersensitive reaction due to immune reaction and, in such a situation, cannot be administered in repeated doses as a agent.
Patent Document 1 describes a polymeric derivative in which a cytidine derivative is bound to a polyethylene glycol, and Non-Patent Document 3 describes a polymeric derivative in which cytarabine is bound to aspartic acid in a polyethylene glycol having the aspartic acid substituted in a branched form at both ends thereof. However, there is also a problem of the possibility that the therapeutic effects of these polymeric derivatives in the clinical are greatly affected by individual difference among patients since the agent release from the derivatives largely depends on hydrolysis reaction by in-vivo enzyme.
Patent Document 2 describes that molecules in each of which an agent is bound to a block-type polymer obtained by condensation of a polyethylene glycol with polyaspartic acid form micelles to provide a medicine. In addition, Patent Document 3 describes a polymer in which an anticancer substance is bound to glutamic acid side chain carboxyl groups of a block-type polymer obtained by condensation of a polyethylene glycol with polyglutamic acid. However, these Patent Documents describe no cytidine antimetabolites as bound agents.
Non-Patent Document 1: Cancer Science, Japanese Cancer Association, Vol. 95, p. 105-111 (2004)
Non-Patent Document 2: Cancer Research, American Association for Cancer Research, Vol. 44, p. 25-30 (1984)
Non-Patent Document 3: Journal of Controlled Release (Elsevier, England), Vol. 79: p. 55-70 (2002)
Patent Document 1: Japanese Patent Application Laying Open (KOHYO) No. Patent Document 2: Japanese Patent No. 2694923
Patent Document 3: Japanese Patent Application Laying Open (KOKAI) No.